Arsenical compounds have been used in the past as therapeutic agents for the treatment of disease. However, the inherent toxicities of arsenical compounds and their generally unfavourable therapeutic index have essentially precluded their use as pharmaceutical agents.
Organo-arsenoxide compounds have been disclosed in WO 01/21628. Such compounds are described as having antiproliferative properties useful in the therapy of proliferative diseases. WO 04/042079 discloses the use of organo-arsenoxide compounds for inducing the mitochondrial permeability transmission (MPT) and the use of organo-arsenoxide compounds for inducing apoptosis, particularly in endothelial cells. The organo-arsenoxide compounds described in WO 01/21628 and WO 04/042079 have a substantially cell-membrane impermeable pendant group linked via a linking group to an arsenoxide group. Neither WO 01/21628 nor WO 04/042079 specifically disclose compounds of formula (I) according to the present invention.
Patients with acute promyelocytic leukaemia (APL) can suffer relapse following treatment with the current therapy, all-trans retinoic acid. In such cases, arsenic trioxide is considered the treatment of choice (Reiter et al., 2004). Arsenic trioxide is a trivalent arsenical that selectively kills APL cells. Arsenic trioxide is also showing promise for the treatment of myelodysplastic syndrome (Vey, 2004), a disease for which no standard treatment currently exists.
However, inorganic arsenicals, such as arsenic trioxide, have long been recognised as a poison and carcinogen when present in the body at levels that exceed its capacity to detoxify the metalloid and are associated with many adverse side effects.
There is a need for alternative therapies for treating proliferative diseases, such as cancer (including treatment of solid tumors), and related conditions. In particular, there is a need for alternative therapies for treating APL, including acute myelocytic leukaemia (AML). There is also a need for a therapeutic treatment for myelodysplastic syndrome.
The present invention relates to a group of arsenoxide compounds comprising an optionally substituted amino acid residue linked via a linking group to a phenylarsenoxide group. Compounds according to the present invention may have one or more advantage(s) over known arsenical compounds, such as arsenic trioxide and the arsenoxide compounds disclosed in WO 01/21628 or WO 04/042079, including the compound 4-(N—(S-glutathionylacetyl)amino)phenylarsenoxide (GSAO), particularly when used for the treatment of proliferative disease, such as cancer (e.g., solid tumors).